Developmental tissues go through regression, remodeling, and apoptosis. In these processes, macrophages phagocytize dead cells and induce apoptosis directly. In hyaloid vascular system (HVS), macrophages induce apoptosis of vascular endothelial cells (VECs) by cooperation between the Wnt and angiopoietin (Ang) pathways through cell-cell interaction. However, it remains unclear how macrophages are activated and interact with VECs. Here we show that Ninjurin1 (nerve injury-induced protein; Ninj1) was temporally increased in macrophages during regression of HVS and these Ninj1-expressing macrophages closely interacted with hyaloid VECs. Systemic neutralization using an anti-Ninj1 antibody resulted in the delay of HVS regression in vivo. We also found that Ninj1 increased cell-cell and cell-matrix adhesion of macrophages. Furthermore, Ninj1 stimulated the expression of Wnt7b in macrophages and the conditioned media from Ninj1-overexpressing macrophages (Ninj1-CM) decreased Ang1 and increased Ang2 in pericytes, which consequently switched hyaloid VEC fate from survival to death. Collectively, these findings suggest that macrophages express Ninj1 to increase the death signal through cell-cell interaction and raise the possibility that Ninj1 may act similarly in other developmental regression mediated by macrophages.

Endometriosis is a major cause of infertility and pelvic pain, affecting more than 10% of reproductive-aged women. Progesterone resistance has been observed in the endometrium of women with this disease, as evidenced by alterations in progesterone-responsive gene and protein expression. cAMP-Response Element-Binding 3-like protein 1 (Creb3l1) has previously been identified as a progesterone receptor (PR) target gene in mouse uterus via high density DNA microarray analysis. However, CREB3L1 function has not been studied in the context of endometriosis and uterine biology. In this study, we validated progesterone (P4) regulation of Creb3l1 in the uteri of wild-type and progesterone receptor knockout (PRKO) mice. Furthermore, we observed that CREB3L1 expression was significantly higher in secretory phase human endometrium compared to proliferative phase and that CREB3L1 expression was significantly decreased in the endometrium of women with endometriosis. Lastly, by transfecting CREB3L1 siRNA into cultured human endometrial stromal cells (hESCs) prior to hormonal induction of in vitro decidualization, we showed that CREB3L1 is required for the decidualization process. Interestingly, phosphorylation of ERK1/2, critical factor for decidualization, was also significantly reduced in CREB3L1-silenced hESCs. It is known that hESCs from patients with endometriosis show impaired decidualization and that dysregulation of the P4-PR signaling axis is linked to a variety of endometrial diseases including infertility and endometriosis. Therefore, these results suggest that CREB3L1 is required for decidualization in mice and humans and may be linked to the pathogenesis of endometriosis in a P4-dependent manner.

A 77 year old woman was admitted to the hospital because of dyspnoea and dizziness for 3 hours. Upon physical examination, her blood pressure was 80/40 mm Hg, with a regular pulse rate of 33 beats per minute. The ECG on admission exhibited P waves with a rate of 100 beats/min and a positive pattern in leads II, III and aVF, third degree atrioventricular (AV) block, AV dissociation with a ventricular rate of 33 beats/min, an 80-ms wide QRS complex, and QT interval of 640 ms (panel A). Temporary percutaneous pacing was begun immediately, resulting in a prompt improvement in the stabilisation of the haemodynamic status. The laboratory findings included a serum potassium level of 7.99 mEq/l, sodium 137.1 mEq/l, urea nitrogen 46.62 mg/dl, and creatinine 3.22 mg/dl. The arterial blood gas analysis revealed a pH of 7.41, pO 2 74.0 mm Hg, and pCO 2 31.8 mm Hg. Her blood potassium level decreased rapidly, and after 2 hours of being treated with a glucose solution, insulin and bicarbonate, it became 5.03 mEq/l. At that time her ECG exhibited normal sinus rhythm (panel B).Hyperkalaemia induced complete AV block without prolongation of the QRS complex is a rare condition. Hyperkalaemia can be responsible for a wide spectrum of electrocardiographic abnormalities. In general, hyperkalaemia produces a gradual depression of the excitability, conduction velocity of the specialised pacemaker cells and conducting tissues throughout the heart. High serum potassium levels are thought to impair the conduction in the Purkinje fibers and ventricles more than in the AV node, although complete atrioventricular block can occur. In this case temporary pacing and excretion of the excessive levels of the serum potassium were essential.

Progesterone (P4) and its cognate receptor, the progesterone receptor (PGR), have important roles in the establishment and maintenance of pregnancy in the murine uterus. In previous studies, using high-density DNA microarray analysis, we identified a subset of genes whose expression is repressed by chronic P4-PGR activation in the uterus. The Clca3 gene is one of the genes whose expression is the most significantly downregulated by P4 and PGR. In the present study, we performed real-time RT-PCR and in situ hybridization to investigate the regulation of Clca3 by P4 and determine the pattern of expression of Clca3 in the uterus during early pregnancy. This analysis shows that Clca3 mRNA transcripts were detected in the luminal and glandular epithelium of the pseudopregnant uterus at day 0·5 and that the expression of Clca3 was not detected after day 3·5. P4 represses Clca3 mRNA synthesis in the luminal epithelial and glandular epithelial cells of the uterus in ovariectomized wild-type mice, but not in Pgr knockout (PRKO) mice. Conversely, estrogen (E2) induces Clca3 expression in the luminal epithelium and glandular epithelium, and this induction was repressed by P4 in the murine uterus. Analysis of the promoter region of Clca3 by in silico and transient transfection analysis in HEC-1A cells identified the regulation of Clca3 by estrogen receptor-alpha (ESR1) within the first 528 bp of 5 -flanking region of the Clca3 gene. Our studies identified Clca3 as a novel downregulated gene of PGR that is a direct target of E2 regulation.